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Many variants of uncertain significance (VUS) have been identified in breast cancer 2 (BRCA2) through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined.

A new test recently developed shows which mutations in the BRCA2 gene make women susceptible to developing breast or ovarian cancers. The laboratory-based test can establish which inherited mutations called VUS in the BRCA2 gene are involved in cancer.

Scientists at the Mayo Clinic (Rochester, MN, USA) and their colleagues conducted a comprehensive assessment of VUS in the BRCA2 C-terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity.

Among 139 variants evaluated, 54 had equal to or greater than 99% probability of pathogenicity, and 73 had equal to or greater than 95% probability of neutrality. Functional assay results were compared with predictions of variant pathogenicity from the Align-GVGD protein-sequence-based prediction algorithm, which has been used for variant classification. Relative to the HR assay, Align-GVGD significantly over-predicted pathogenic variants.

The team subsequently combined functional and Align-GVGD prediction results in a Bayesian hierarchical model (VarCall) to estimate the overall probability of pathogenicity for each VUS. In addition, to predict the effects of all other BRCA2 DBD variants and to prioritize variants for functional studies, they used the endoPhenotype-Optimized Sequence Ensemble (ePOSE) algorithm to train classifiers for BRCA2 variants by using data from the HR functional assay.

Fergus J. Couch, PhD, the senior investigator of the study said, “Up until now, it has only been possible to establish that 13 inherited mutations in BRCA2 are pathogenic and known to cause cancer. In this study, we identified 54 that increase the risk of cancer. Similarly, 21 known neutral mutations that do not increase risk of cancer can now be expanded to 73. These findings may help patients and their health care providers make better decisions about how to deal with information obtained through genetic testing.” The study was published on January 25, 2018, in the American Journal of Human Genetics.